Summary.  Background: Prevention of arthropathy is a major goal of hemophilia treatment. While studies in adults have demonstrated an impact of prophylaxis on the incidence of joint bleeds and patients’ well‐being in terms of improved quality of life (QoL), it is unclear whether or not prophylaxis influences the outcome and perception of well‐ of children with hemophilia. Objective: This randomized controlled study compared the efficacy of prophylaxis with episodic therapy in preventing hemarthroses and image‐proven joint damage in children with severe hemophilia A (factor VIII <1%) over a 10‐year time period. Methods: Forty‐five children with severe hemophilia A, aged 1–7 years (median 4), with negative clinical‐radiologic joint score at entry and at least one bleed during the previous 6 months, were consecutively randomized to prophylaxis with recombinant factor VIII (25 IU kg−1 3 × week) or episodic therapy with ≥25 IU kg−1 every 12–24 h until complete clinical bleeding resolution. Safety, feasibility, direct costs and QoL were also evaluated. Results: Twenty‐one children were assigned to prophylaxis, 19 to episodic treatment. Children on prophylaxis had fewer hemarthroses than children on episodic therapy: 0.20 vs. 0.52 events per patient per month (P < 0.02). Plain‐film radiology showed signs of arthropathy in six patients on prophylaxis (29%) vs. 14 on episodic treatment (74%) (P < 0.05). Prophylaxis was more effective when started early (≤36 months), with patients having fewer joint bleeds (0.12 joint bleeds per patient per month) and no radiologic signs of arthropathy. Conclusion: This randomized trial confirms the efficacy of prophylaxis in preventing bleeds and arthropathy in children with hemophilia, particularly when it is initiated early in life.

Helicobacter pylori chronically colonizes the stomach and duodenum and causes peptic ulcers or gastric adenocarcinoma in 10 to 20% of infected individuals. We hypothesize that the inability of patients to clear H. pylori infections is a consequence of active suppression of the immune response. Here we show that H. pylori-infected individuals have increased frequencies of CD4؉ CD25 high T cells in both the stomach and duodenal mucosa compared to uninfected controls. These cells have the phenotype of regulatory T cells, as they express The gastrointestinal mucosa is in constant contact with both harmless and harmful antigens. The immune system has to discriminate between these antigens to maintain a balance between active defense and the prevention of immunopathology. In mouse models, naturally occurring CD4 ϩ CD25 ϩ regulatory T cells (T reg cells) have been implicated in playing an important role in suppressing immune responses to the normal intestinal flora (28) as well as to pathogens (22,25). However, little is currently known about the role of T reg cells in the human gastrointestinal mucosa.Most studies of human T reg cells have been performed with cells isolated from peripheral blood (2, 17, 32), but CD4 ϩ CD25ϩ cells with suppressor activity have also been demonstrated in the thymus (29), cord blood (36), synovial fluid (4), tonsils (32), and a few types of tumors (19,37). Human T cells have a more variable expression of CD25 (the interleukin-2 receptor ␣-chain) than do mouse T cells, and only those that express CD25 with the highest intensities (CD25 high ) are suppressive (2, 4). T cells expressing intermediate levels of CD25 (CD25 low ) are instead activated effector or memory T cells and lack a regulatory function. T reg cells suppress the activity of other T cells via a contact-dependent mechanism, but the molecules directly mediating this suppression have still not been clearly identified (22). However, the Foxp3 gene (FOXP3 in humans), which encodes the transcription factor scurfin, has recently been demonstrated to be a key regulatory gene for the development and function of T reg cells (10,15,16). Humans with defects in the FOXP3 gene experience strong activation of the immune system, leading to multiorgan autoimmune disease, inflammatory bowel disease, allergies, and severe infections, collectively known as the IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, X-linked inheritance syndrome) (11). FOXP3/Foxp3 is expressed by CD4 ϩ CD25ϩ T reg cells in humans and mice, and the transduction of CD25 Ϫ cells from mice with this gene converts the cells into regulatory cells. Although recent data indicate that FOXP3 gene expression can be induced in CD25Ϫ cells under special conditions (5, 9, 33, 34), these induced FOXP3-expressing cells also have a suppressive capacity, suggesting that a tight link exists between FOXP3 expression and a regulatory function.We are currently investigating the role of T reg cells in chronic Helicobacter pylori infection (20,25). Although H. pylori colo...

Helicobacter pylori colonizes the gastric and duodenal mucosa. The infection normally persists for life and causes peptic ulcers and gastric cancer in a subset of infected individuals. We hypothesized that the inability to clear the infection may be a consequence of H. pylori-specific regulatory T cells that actively suppress T-cell responses. Therefore, we characterized the T-cell responses to H. pylori in H. pylori-infected individuals without any subjective symptoms and in uninfected control subjects and investigated the role of regulatory CD4

Evaluation of prophylactic treatment of haemophilia requires sensitive methods. To design and test a new magnetic resonance imaging (MRI) scale for haemophilic arthropathy, two scales of a combined MRI scoring scheme were merged into a single scale which includes soft tissue and osteochondral subscores. Sixty-one joint MRI's of 46 patients with haemophilia were evaluated by four radiologists using the new and older scales. Forty-six of the joints were evaluated using two X-ray scales. For all MRI scores, interreader agreement and correlations with X-ray scores and lifetime number of haemarthroses were analysed. The interreader agreement intraclass correlation coefficient was 0.82, 0.89 and 0.88 for the soft tissue and osteochondral subscores and the total score, as evaluated according to the new MRI scale, compared to 0.80 and 0.89 as for the older scales. The total score and osteochondral subscore according to the new scale, as well as scores according to the older scales were correlated (P < 0.01) with number of haemarthroses (Spearman correlation 0.35-0.68) and with the X-ray scores (Spearman correlation 0.40-0.76), but no correlation (P > 0.05) was found between the soft tissue subscore of the new MRI scale and the X-ray scores. The new MRI scale is simpler to apply than the older and has similar reader reliability and correlation with lifetime number of haemarthroses, and by separating soft tissue and osteochondral changes it gives additional information. The new scale is useful for analyses of early and moderate stages of arthropathy, and may help to evaluate prophylactic haemophilia treatment.

Background Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives To describe 3-year bleeding, joint health and structure, health-related quality-of-life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods Males aged 12-50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible.

Summary. In a European multicentre study, 39 ankles in 28 haemophilic boys were investigated by magnetic resonance imaging (MRI). A new MRI score was developed in the format A(e:s:h) for evaluating haemophilic arthropathy. This scheme provides high resolution and allows separation of different pathological components. The factor A is calculated as the sum of scores for subchondral cysts (maximum value 6), irregularity/erosion of subchondral cortex (maximum 4) and chondral destruction (maximum 6); e, s and h, respectively, represent effusion/haemarthrosis, synovial hypertrophy and haemosiderin deposition, and they are separately evaluated on a scale of 0-4. Working independently, two radiologists scored the 39 ankles twice using both this new ÔEuropeanÕ scoring method and a previously published ÔDenverÕ scoring scheme. Final classification was achieved by consensus. The reproducibility of the readings was assessed, and for both scoring methods the results indicated good or moderate intraobserver agreement, and good, moderate or fair interobserver agreement. These findings suggest that MRI can be useful for semiquantitative evaluation of haemophilic arthropathy, providing the examination is performed according to an appropriate protocol, and the images are evaluated by specially trained radiologists.

In natural habitats, plants frequently experience rapid changes in the intensity of sunlight. To cope with these changes and maximize growth, plants adjust photosynthetic light utilization in electron transport and photoprotective mechanisms. This involves a proton motive force (PMF) across the thylakoid membrane, postulated to be affected by unknown anion (Cl−) channels. Here we report that a bestrophin-like protein from Arabidopsis thaliana functions as a voltage-dependent Cl− channel in electrophysiological experiments. AtVCCN1 localizes to the thylakoid membrane, and fine-tunes PMF by anion influx into the lumen during illumination, adjusting electron transport and the photoprotective mechanisms. The activity of AtVCCN1 accelerates the activation of photoprotective mechanisms on sudden shifts to high light. Our results reveal that AtVCCN1, a member of a conserved anion channel family, acts as an early component in the rapid adjustment of photosynthesis in variable light environments.

The international MRI expert subgroup of the International Prophylaxis Study Group (IPSG) has developed a consensus for magnetic resonance imaging (MRI) scales for assessment of haemophilic arthropathy. A MRI scoring scheme including a 10 step progressive scale and a 20 step additive scale with identical definitions of mutual steps is presented. Using the progressive scale, effusion/haemarthrosis can correspond to progressive scores of 1, 2, or 3, and synovial hypertrophy and/or haemosiderin deposition to 4, 5, or 6. The progressive score can be 7 or 8 if there are subchondral cysts and/or surface erosions, and it is 9 or 10 if there is loss of cartilage. Using the additive scale, synovial hypertrophy contributes 1-3 points to the additive score and haemosiderin deposition contributes 1 point. For osteochondral changes, 16 statements are evaluated as to whether they are true or false, and each true statement contributes 1 point to the additive score. The use of these two compatible scales for progressive and additive MRI assessments can facilitate international comparison of data and enhance the accumulation of experience on MRI scoring of haemophilic arthropathy.